DESCRIPTION (Verbatim from applicant?s abstract): Kallmann?s neurological syndrome is a genetic disorder characterized by severe defects in axon targeting in the olfactory system. Associated anomalies include neurosensory hearing loss, mental retardation, color blindness, motor epilepsy, cerebellar ataxia, spastic paraplegia, and synkinesia. The X-Iinked forms of the disease affect 1/10,000 males and are caused by mutations in the gene KAL-1, which codes for a cell-surface protein with several protein-protein interaction motifs. The molecular mechanisms of KAL-1 action, such as receptors and signal transducers, are unknown. To gain insight into KAL-1 function, one can turn to its C. elegans ortholog, which is neuronally expressed. This research proposes to determine the endogenous role and to identify interacting molecules of CeKAL-1 in C.elegans. The method of RNA interference (ANAl) will be used to generate a loss of function in CeKAL-1 which will be systematically investigated for neuronal defects. Other evidence implicating CeKAL-1 in neural development comes from ectopic misexpression of CeKAL-1, which results in specific axonal outgrowth and pathfinding defects. To identify interacting molecules of CeKAL-1, a modifier screen of one such phenotype was performed and yielded several mutant loci. Some of these may define proteins that interact endogenously with CeKAL-1, such as co-factors, receptors, or signal transducers. To determine which mutant loci may be specific interactors with CeKAL-1, this research proposes to systematically analyze their neuronal phenotypes and efficacy in suppressing distinct CeKAL-1 misexpression phenotypes. Once one or more CeKAL-1 modifier loci have been determined to be of specific interest, cloning and further characterization will be pursued.